The present invention relates to a process for the purification of diphenyl ether compounds which are useful as herbicides or as intermediates in the synthesis of herbicides. In particular, it relates to a process for obtaining particular nitrated isomers of diphenyl ether compounds from mixtures containing other nitrated isomers.
Diphenyl ether herbicides are known, for example from EP-A-0022610 which relates to herbicides of the formula: 
wherein X and Y may be H, F Cl, Br, CF3, OCF2CHZ2 (Z=Cl, Br, F), OCH3, CN, CO2R (R=lower alkyl), C6H5, O-alkyl, NO2 or SO2 lower alkyl;
and also describes a process for making these compounds by nitrating a compound of the formula: 
wherein X and Y are as defined above.
Suggested nitrating agents for this reaction include mixtures of nitric and sulphuric acids and the recommended reaction solvent is dichloromethane. The nitration process is said to give a yield of 75.4% but no details are given of the purity of the product or the presence of other nitrated isomers.
U.S. Pat. No. 4,031,131 describes similar compounds to the above which are prepared in a similar manner. Suggested nitrating agents include potassium nitrate or mixed nitric and sulphuric acids and the reaction is carried out in dichloromethane. An extremely high yield ( greater than 95%) is claimed for the nitration reaction but, again, there are no details given about the purity of the product. Nitration reactions using mixed nitric and sulphuric acids may also be carried out in the presence of acetic anhydride.
EP-A-0003416 and EP-A-0274194 both relate to the synthesis of herbicidal compounds of the formula: 
wherein
R1 is alkyl optionally substituted with fluorine or optionally substituted phenyl;
R3 is H, F, Cl, Br, I alkyl, trifluoromethyl or CN;
R4 is H, F, Cl, Br, I or trifluoromethyl;
R5 is F, Cl, Br, I or trifluoromethyl; and
R6 is H or C1-C4 alkyl.
In EP-A-0003416, these compounds may be obtained by nitrating the corresponding carboxylic acid or carboxamide and then converting to the sulphonamide or by nitrating the sulphonamide itself. A nitration reaction is described in Example 7 where the solvent is 1,2-dichloroethane and the nitrating agent is a mixture of potassium nitrate and concentrated sulphuric acid.
EP-A-0274194 relates, in particular, to a process for the nitration of compounds of the formula: 
The nitration reaction is said to be carried out using a conventional nitrating agent such as concentrated nitric acid or sodium nitrate or mixtures of these with sulphuric acid. The reaction solvent is one which is resistant to nitration and examples of such solvents are said to include halogenated solvents such as dichloromethane, dichloroethane, dichloropropane, chlorofluorocarbons and aromatic solvents such as nitrobenzene.
However, none of these methods are particularly satisfactory for use on an industrial scale because they all have the common problem that the reaction yields a mixture of the required product and other nitrated isomers. Nitrated isomers of diphenyl ether compounds are often extremely difficult to separate from one another and the quantity of other isomers is often too high for the final product to fulfil the requirements of the regulatory authorities for herbicides. The problem tends to be further exacerbated if the nitrated product is an intermediate in the synthesis of a herbicide rather than the required herbicide itself because the mixture of nitrated compounds means that larger quantities of other reagents must be used than would be necessary if the nitrated isomers could be separated satisfactorily. It is therefore important to ensure that the nitration process produces a product mixture containing the highest possible proportion of the desired isomer.
The problem of obtaining mixtures of isomers from the nitration process was recognised by the authors of GB-A-2103214 who describe a process in which a compound of the formula: 
wherein each of
X1, X2, and X3, is H, fluorine, chlorine, bromine, CF3, O CF2,CHZ2 (where Z is F, Cl or Br), OCF3, CN, COOR (R is lower alkyl), phenyl, lower alkoxy or NO2R and at least one of X1, X2, and X3 is other than hydrogen; and
Y is COOR or carboxy;
is nitrated to give a product of the formula: 
wherein X1, X2, X3 and Y are as defined above. The document relates especially to Acifluorfen, the compound in which X1 is 2-chloro, X2 is 4-trifluoromethyl, X3 is hydrogen and Y is COOH.
According to this prior art document, the product is purified by selectively dissolving unwanted isomers and other by-products in a suitable solvent. Examples of solvents which are said to be suitable for this purpose include hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, cycloheptane, benzene, toluene, xylenes and mixtures of xylenes, ethylbenzene, cumene, pseudo-cumene, ethyl-toluene and trimethylbenzene. Alternatively, it is suggested that chlorohydrocarbons may be used and examples given are 1,2-dichloroethane, methylene chloride, chloroform and chlorobenzene. Xylenes appear to be especially preferred and suggested amounts are about 0.35 to 0.45 moles of xylenes per mole of crude Acifluorfen. The crude nitration product is dissolved in the chosen solvent at elevated temperature and maintained at this temperature for a considerable period of time. On cooling, Acifluorfen crystallises out and is collected by centrifugation. The product obtained by the authors of GB-A-2103214 is said to be 82% pure.
However, the present inventors have found that the process described in GB-A-2103214, although partially effective, does not appear to give material of this degree of purity. In any case, it is desirable to be able to obtain material of an even greater degree of purity than specified in the prior art, particularly if additional process steps are required in order to obtain the required herbicidal compound.
Therefore in a first aspect of the present invention there is provided a process for the purification of a compound of general formula I: 
wherein:
R1 is hydrogen or C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl (any of which may potionally be substituted with one or more substituents selected from halogen and OH) or COOH, COH, COOR4, COR6, CONR4R5 or CONHSO2R4;
R4 and R5 are each independently hydrogen or C1-C4 alkyl optionally substituted with one or more halogen atoms;
R6 is a halogen atom or a group R4;
R2 is hydrogen or halo;
R3 is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, any of which may optionally be substituted with one or more halogen atoms, or halo;
or, where appropriate, a salt thereof;
from a mixture containing the compound of general formula I together with one or more isomers or di-nitrated analogues thereof;
the process comprising dissolving the mixture in a suitable crystallising solvent and recrystallising the product from the resulting crystallisation solution;
characterised in that the crystallisation solution contains not more than 25% loading of the compound of general formula I and in that the temperature to which the solution is cooled for crystallisation is not greater than about 30xc2x0 C.
In the present specification, loading is defined as:       weight    ⁢          xe2x80x83        ⁢    of    ⁢          xe2x80x83        ⁢    pure    ⁢          xe2x80x83        ⁢    compound    ⁢          xe2x80x83        ⁢    of    ⁢          xe2x80x83        ⁢    formula    ⁢          xe2x80x83        ⁢    I    xc3x97    100              weight      ⁢              xe2x80x83            ⁢      of      ⁢              xe2x80x83            ⁢      pure      ⁢              xe2x80x83            ⁢      compound      ⁢              xe2x80x83            ⁢      of      ⁢              xe2x80x83            ⁢      formula      ⁢              xe2x80x83            ⁢      I        +          weight      ⁢              xe2x80x83            ⁢      of      ⁢              xe2x80x83            ⁢      solvent      
In order to calculate the loading of the crystallisation solution, it is therefore essential to know the amount of isomer of general formula I present in the product mixture.
Using the process of the present invention, it is possible to obtain a product of greater than 90% purity. This is a significant advantage when the product is a herbicide as regulatory authorities usually demand an active ingredient of a very high level of purity with minimal impurities. The advantage may be even greater when the product produced is an intermediate and additional steps must be carried out as reagents are not wasted in reacting with unwanted by-products.
The process of the present invention differs significantly from the process described in. GB-A-2103214. The authors of that document stated that, for xylenes, the optimum amount of product loading is from 0.35 to 0.45 moles of xylene per mole of Acifluorfen. This is a solution containing at least 88% w/w of Acifluorfen whereas, in the present invention, the crystallisation solution contains not more than 25% loading of Acifluorfen. In a typical crude mixture containing about 70% Acifluorfen, this corresponds to a crystallisation solution containing about 32% w/w of the crude mixture.
In the context of the present invention, compounds of general formula I are designated 4xe2x80x2-nitro isomers.
Other components of the product mixture which may be present include the 2xe2x80x2-nitro isomer of general formula: 
the 6xe2x80x2-nitro isomer: 
and the dinitro isomers (1) and (2): 
A further unwanted by-product formed by nitration of an isomer present as an impurity in the reactant is (3): 
It is particularly important that purification of the desired product of general formula I should remove all, or substantially all, of the 2xe2x80x2-nitro isomer since this is the most difficult isomer to separate from the product by other methods. In addition, if the compound of general formula I is to be used as starting material in a further reaction, other nitrated isomers are also likely to react and this causes wastage of reagents. Again, the 2xe2x80x2-nitro isomer is a particularly important impurity as many of its reaction products are also difficult to separate from the reaction products of compounds of general formula I.
In the context of the present invention, the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a saturated straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, t-butyl, n-pentyl and n-hexyl. The term xe2x80x9cC1-C4 alkylxe2x80x9d is a subset of C1-C6 alkyl and refers to an alkyl group having up to 4 carbon atoms.
The term xe2x80x9cC2-C6 alkenylxe2x80x9d refers to a straight or branched hydrocarbon chain containing from 2 to 6 carbon atoms and having at least one double bond. Examples include ethenyl, allyl, propenyl and hexenyl. The term xe2x80x9cC2-C4 alkenylxe2x80x9d is a subset of C2-C6 alkenyl and refers to an alkenyl group having up to 4 carbon atoms.
The term xe2x80x9cC2-C6 alkynylxe2x80x9d refers to a straight or branched hydrocarbon chain containing from 2 to 6 carbon atoms and having at least one triple bond. Examples include ethynyl, propynyl and hexynyl. The term xe2x80x9cC2-C4 alkynylxe2x80x9d is a subset of C2-C6 alkynyl and refers to an alkynyl group having up to 4 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine or iodine and the corresponding term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo or iodo.
Only a narrow range of solvents is suitable for use in the present invention with examples being aromatic hydrocarbons, such as xylenes or mixtures of xylenes, and haloaromatics such as o-chlorotoluene, p-chlorotoluene, benzotrifluoride, 3,4-dichlorobenzotrifluoride, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, bromobenzene, and 2-fluorotoluene. Mixtures of any of the above solvents may also be suitable and also mixtures containing aromatic hydrocarbons with a co-solvent which may be one of the solvents mentioned above but may, alternatively be chosen from a much wider range of solvents including aliphatic hydrocarbons, esters, ethers, nitriles and halohydrocarbons.
Xylenes have been found to be particularly suitable solvents for use in the present invention with o-xylene giving better results than other xylenes or mixtures of xylenes.
The optimum loading of the crystallisation varies considerably according to the solvent which is chosen but is, in any case, not greater than about 25%. More typically, optimum loading is from 8% to 20%. For many solvents, for example xylenes, the loading may be, for example, from about 15 to 20% but with a few solvents it is necessary to reduce the loading even further with a product mixture loading of about 8 to 10% being used.
Although the temperature to which the solution is cooled to effect crystallisation may be as high as 30xc2x0 C., the purity of the product may be increased considerably by reducing the temperature somewhat. It is greatly preferred, therefore that the temperature to which the solution is cooled to achieve crystallisation is not above 20xc2x0 C., with about 5xc2x0 to 15xc2x0 C. being an optimal range. This is in contrast to the process described in GB-A-2103214 in which the crystallisation temperature recommended for optimum results is about 25xc2x0 C.
A further factor which has been found to affect the purity of the product is the length of time for which the mixture is allowed to stand after crystallisation before recovery of the product. It has been found that many 2xe2x80x2-nitro isomers of general formula I are metastable in solution and tend to crystallise slowly, contaminating the desired product and reducing its purity after crystallisation. Therefore, it is preferred that the product slurry, after achieving crystallisation temperature, is not held for more than about four hours, more usually from about 1 to 2 hours, before physical separation of the product from the mother liquors.
Crystallisation may be achieved by any suitable method such as seeding the crystallisation solution with crystals of a pure compound of general formula I. It may be advantageous to carry out the seeding in several stages starting when the crystallisation solution is still hot and adding further crystals as it cools. In some circumstances, seeding of the crystallisation solution may not be necessary and cooling of the solution will cause crystallisation of the product.
The product may be separated from the slurry after crystallisation by any appropriate method but filtration is very often the most convenient way of doing this.
The mixture to be purified may be the crude product of a process for the nitration of a compound of general formula II: 
wherein R1, R2 and R3 are as defined for general formula I.
Any conventional nitration method may be used, for example the nitration method disclosed in GB-A-2103214.
In one suitable method, the nitration agent may be nitric acid or a mixture of nitric and sulphuric acids although other types of nitrating agent may also be used. The reaction may take place in an organic solvent and suitable solvents include halogenated solvents such as dichloromethane (DCM), ethylene dichloride (EDC), chloroform, tetrachloroethylene (perklone) and dichlorobenzotrifluoride (DCBTF). Alternatively, solvents such as acetic acid, acetic anhydride, acetonitrile, ethers such as tetrahydrofuran (THF) or dioxane, sulpholane, nitrobenzene, nitromethane, liquid sulphur dioxide or liquid carbon dioxide. It is also advantageous to conduct the reaction in the presence of acetic anhydride and, in this case, it is preferred that the molar ratio of acetic anhydride to compound of general formula II is from about 1:1 to 3:1. The reaction temperature may be from about xe2x88x9215xc2x0 to 15xc2x0 C., more usually from about xe2x88x9210xc2x0 to 10xc2x0 C.
After the nitration reaction, the crude product must be removed from the reaction solvent and taken up in the crystallisation solvent. This may be achieved by washing with water to remove any acetic anhydride, acetic acid or mineral acid and then stripping off the reaction solvent completely, melting the product mixture and then taking up the melt in the crystallisation solvent. Alternatively, the product can be extracted from the nitration solvent as a salt (for example the sodium salt) into water and the solvent separated off for recycling. The salt solution may then be acidified in the presence of the hot recrystallisation solvent in order to extract the product for recrystallisation.
When the nitration process is combined with either of these work-ups and the recrystallisation process of the first aspect of the invention, it is possible to obtain a product of over 90% purity in a yield of greater than 70%.
The step of taking up the crude product in the crystallisation solvent may be preceded by an initial partial purification step which itself forms a further aspect of the present invention.
In this aspect of the invention, there is provided a process for partial purification of a product mixture obtained from the nitration of a compound of general formula II to give a compound of general formula I, the process comprising removing the reaction solvent and treating the resultant crude product with a mixture of water and a water-miscible polar solvent.
In one method of achieving partial purification, any acetic anhydride may be hydrolysed with water to give acetic acid and this, or acetic acid from any other source, may be left in the reaction mass to act as the polar solvent. The reaction solvent may then be removed by distillation or steam distillation leaving a molten crude product containing some acetic acid which may then be treated with additional quantities of acetic acid and water to facilitate partial purification without substantial dissolution of the required isomer.
Alternatively, the crude product of the nitration reaction, after washing and removal of the reaction solvent, may be treated with a mixture of a polar solvent and water to achieve partial dissolution of impurities and isomers without substantial loss of the desired product which can then be recovered by filtration. In this case, suitable polar solvents include solvents such as formic acid, acetic acid, propionic acid, methanol, acetonitrile and acetone.
The proportion of polar solvent to water may be in the range of from about 3:7 to 7:3, more particularly from about 2:3 to 3:2, and the amount of crude nitrated isomer mixture in the polar solvent/water solution may be from about 10 to 80% by weight, preferably about 15 to 30% by weight. The initial purification step may be carried out at a temperature of from about 10xc2x0 to 60xc2x0 C., more usually from about 15xc2x0 to 30xc2x0 C.
An initial purification process such as those described above leads to an improvement in the quality of the crude nitration product from about 70% strength (i.e. 70% by weight of the desired isomer of general formula I) to about 80% strength. A nitration process followed by the initial purification step and the recrystallisation process of the first aspect of the invention is high yielding with a recovery of the desired isomer of greater than 90% and often greater than 95%. The initial purification step of the second aspect of the invention is particularly effective for the removal of products of over nitration and also other impurities which commonly occur in a product derived from a multi-step synthesis. The product from the initial purification process has improved characteristics for purification by recrystallisation.
Although the process of the invention may be used for the purification of any compound of general formula I, it is especially preferred that R2 is chloro and R3 is trifluoromethyl. Particularly preferred compounds of general formula I are those in which R1 is COOH or CONHSO2CH3. These compounds are 5-(2-chloro-xcex1,xcex1,xcex1-trifluoro-4-tolyloxy)-2xe2x80x2-nitrobenzoic acid (Acifluorfen) and 5-(2-chloro-xcex1,xcex1,xcex1-trifluoro-4-tolyloxy)-N-methanesulphonyl-2xe2x80x2-nitro-benzamide (Fomesafen), both of which are potent herbicidal compounds.
In addition to being a herbicide in its own right, Acifluorfen may also serve as an intermediate in the synthesis of Fomesafen. The Acifluorfen may be converted to the acid chloride which may then be reacted with methane sulphonamide to give Fomesafen. Both of these steps may be carried out by conventional methods, for example as set out in EP-A-0003416. It is a particular advantage when using this method to start out with pure Acifluorfen as the reaction with methane sulphonamide is an expensive process and it is highly desirable not to waste reagents by sulphonamidating unwanted nitro-isomers to produce unwanted isomers of Fomesafen.
The present invention therefore provides a route for the synthesis of pure Acifluorfen and its subsequent conversion to pure Fomesafen.